This mentored Research Career Development (K08) proposal describes the 5-year training program for Dr. Kibbe. This proposal builds upon the Candidate's strengths and prior research skills and takes advantage of the research scientists at Northwestern University and the National Cancer Institute. Through the mentorship of Drs. David Dean and William Pearce and a structured didactic component, the Candidate's ability to perform hypothesis driven research will be advanced to a fully independent surgeon scientist The broad, long-term objective of this project is to prevent the development of neointimal hyperplasia following arterial injury and vascular bypass surgery. Currently, no effective therapy exists to prevent the development of neointimal hyperplasia. Therefore, the overall goal of this grant is to examine the mechanisms of NO-mediated inhibition of neointimal hyperplasia while also evaluating the clinical utility of biocompatible NO-eluting therapies. We hypothesize that biocompatible NO-eluting therapies will prevent the development of neointimal hyperplasia and that p53, heme oxygenase (HO), and the ubiquitin enzymes play a crucial role in this process. Specific Aim 1: Evaluate the effect of novel NO-eluting gels on the development of neointimal hvperplasia following arterial injury and vein bypass grafting. The rat carotid artery injury model and porcine carotid artery vein bypass model will be used to study the efficacy of the delivery vehicle, the optimal dose, toxicity, and the long-term durability of this therapy. Specific Aim 2: To determine the efficacy of a spontaneously releasing polymer cross-linked NO-eluting PTFE graft on the development of neointimal hvperplasia following prosthetic arterial bypass grafting. A porcine carotid artery bypass model will be used to study the efficacy of the NO-eluting PTFE graft, the optimal concentration, toxicity, and the long-term durability of this therapy. Specific Aim 3: Examine the mechanism by which NO induces VSMC apoptosis. Specifically, we will determine if p53 regulates HO-2 expression through post-transcriptional regulation. Additionally, we will determine which of the end products of heme metabolism by HO-2, namely carbon monoxide (CO), iron, or biliverdin, are responsible for preventing NO-induced VSMC apoptosis. Specific Aim 4: Examine the mechanism by which NO inhibits VSMC proliferation. Specifically, the role of the ubiquitin-activating, -conjugating, and -ligase enzymes in NO-mediated inhibition of VSMC proliferation will be evaluated. The data from this study will serve as the basis for further studies of NO-mediated inhibition of neointimal hyperplasia. (End of Abstract)